Fascaplysin Induces Caspase Mediated Crosstalk Between Apoptosis and Autophagy Through the Inhibition of PI3K/AKT/mTOR Signaling Cascade in Human Leukemia HL‐60 Cells

Abstract

In this study, we for the first time explored the cellular and molecular mechanism of anticancer properties of fascaplysin, a marine sponge-derived alkaloid. Our study demonstrated that fascaplysin induced a cooperative interaction between apoptotic and autophagic pathways to induce cytotoxicity in HL-60 cells. Fascaplysin treatment not only activated pro-apoptotic events like PARP-1 cleavage and caspase activation but also triggered autophagy signaling as shown by the increased expression of LC3-II, ATG7and beclin. Interestingly, it was found that use of pan-caspase inhibitor completely reversed the fascaplysin mediated cell death as analyzed by MTT and cell cycle assays. It was observed that cell death as well as the expression of pro-death proteins was partially reversed, when key autophagy mediators ATG7 was silenced by siRNA in fascaplysin treated cells. Cooperative involvement of autophagy and apoptotic signaling in cytotoxicity was confirmed when combined silencing of pro-apototic (PARP-1) and autophagic (ATG-7) signaling by respective siRNA's lead to substantial rescue of cell death induced by fascaplysin. Although, apoptosis and autophagy are two independent cell death pathways, our findings provide detailed insight by which both the pathways acted cooperatively to elicit fascaplysin induced cell death in HL-60 cells. Our findings provide molecular insight into the anti-cancer potential of fascaplysin by showing that both autophagic and apoptotic signaling can work together in the induction of cell death.

Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation

“…23, 24 Akt and mTOR phosphorylation levels were decreased significantly 2 h after PDT (Figure 5a). Additionally, pre-treatment with the PI3K inhibitor LY294002 or Akt inhibitor triciribine did not affect the expression of p-Akt, p-mTOR and LC3-II (Figure 5b).…”

“…The PI3K/Akt/mTOR signaling pathway is a classic autophagy pathway. 23, 24 PI3K and Akt suppression can inhibit mTOR phosphorylation at the Ser 2448 site, thereby enhancing the expression of autophagy-related proteins and inducing autophagy. 37 To determine whether PDT-induced autophagy occurred through the PI3K/Akt/mTOR pathway, we monitored the Akt and mTOR phosphorylation at different time points after PDT and found that mTOR and Akt phosphorylation significantly decreased after PDT.…”

Triggering of Suicidal Erythrocyte Death by Fascaplysin

“…The marine sponge-derived bis-indole alkaloid Fascaplysin is effective against malaria [1], against bacterial, fungal, and viral infections [1], as well as against malignancy [1][2][3]. The efficacy against malignancy is at least in part due to activation of autophagy and apoptosis of tumor cells [2,3].…”

“…The efficacy against malignancy is at least in part due to activation of autophagy and apoptosis of tumor cells [2,3]. Fascaplysin further counteracts angiogenesis by triggering apoptosis of endothelial cells [4].…”

“…Fascaplysin further counteracts angiogenesis by triggering apoptosis of endothelial cells [4]. Cellular mechanisms involved include inhibition of p56 tyrosine kinase and of cyclin-dependent kinase-4 [1,4], DNA intercalation [1] as well as activation of caspases [2].…”